Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas.
A three-dimensional (3D) quantitative pharmacophore model was developed from a training set of structurally diverse substituted ureas against Raf-1 kinase, which was well validated to be highly predictive by two methods, namely, test set prediction and Cat-Scramble method. Then a virtual database searching was performed with the pharmacophore model as a 3D query, and the bioactivities of the retrieved hits were predicted by the pharmacophore. Subsequently, molecular docking was carried out on the selected hits whose estimated IC(50) was less than 1 microM. Finally, 29 hits were identified as potential leads against Raf-1 kinase, which exhibited good estimated activities, high docking scores, similar binding mode to experimentally proven compounds and favorable drug-like properties. The study may facilitate the discovery and rational design of novel leads with potent inhibitory activity targeting Raf-1 kinase.
Li
Hui-Fang
HF
Department of Organic Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Lu
Tao
T
Zhu
Tian
T
Jiang
Yong-Jun
YJ
Rao
Sha-Sha
SS
Hu
Li-Ye
LY
Xin
Bo-Tao
BT
Chen
Ya-Dong
YD
D003628:Database Management Systems; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D014508:Urea; D019908:Proto-Oncogene Proteins c-raf